We have demonstrated abnormal neuronal migration in the cerebral cortex of mice in which the cyclin-dependent kinase 5 gene has been disrupted. This abnormality has been shown to be a cell-autonomous. Mutations in proteins such as this may underlie abnormal brain development in humans. We have extended our work on Mucolipidosis IV, a human neurodevelomental lysosomal storage disease of unknown etiology. Our findings point to an abnormality of endosomal trafficking in this disorder. We discovered alterations in the brain of these patients consisting of dysgenesis of the corpus callosum and dysmyelination. This disorder is genetically homogeneous. We found that patients from a variety of ethnic backgrounds belong to a single complementation group. In a collaborative study with investigators at the Harvard Institute of Human Genetics, the chromosomal localization of the gene that is mutated in Mucolipidosis IV has been mapped to chromosome 19q13.2-13.3. This is an important step toward the identification of the gene and its product. Because most patients with dysmyelinating diseases cannot yet be classified into discrete clinicopathologic entities, we developed a clinical protocol for the identification of novel leukodystrophies. This work has led to the discovery of three new human leukodystrophy syndromes. The first of these, childhood ataxia with central nervous system hypomyelination (CACH syndrome), is one of the most common leukodystrophies of humans. This disorder has been carefully characterized clinically and morphologically. Work on cloning the involved gene is underway. The second condition is known as ovarioleukodystrophy. It occurs in young women, and it is associated with ovarian dysgenesis. A third unique human leukodystrophy exhibits features of the quaking mouse mutant. The identification of the genes associated with these leukodystrophies will improve our understanding of neurodevelopmental abnormalities and provide a better comprehension of the processes of myelination. It will also provide insight into the development of treatment for such patients. - Neurodevelopmental knock- out murine models; Mucolipidosis IV, CACH Syndrome, Ovarioleukodystrophy, - Human Subjects